To date, the best correlation with synapse loss and cognitive decline in Alzheimer?s disease (AD) has been the aggregation of two proteins: tau and A?. However, this correlation is not perfect, as a cohort of subjects (non- demented with Alzheimer?s like neuropathology or NDAN) has aggregation and accumulation of these proteins without any obvious cognitive deficits or synapse loss. We have found that the kinase MARK4 shows a better correlation with cognitive deficits, having subthreshold levels in controls, some detectable expression in amnestic mild cognitive impairment, high expression in AD, and undetectable expression in NDAN. However, correlation is not causation. Unfortunately, little is known about early causal events that lead to the loss of synapses and their networks in AD, but synapse destabilization, which is essential for disassembling the synapse, is a definite precursor to synapse loss. Our Drosophila data offer strong causal evidence that the Drosophila homolog of MARK4, Par-1, triggers destabilization of synapses. More recently we developed causal evidence in mice that MARK4 potentiates low molecular weight A?-induced deficits in synaptic function. Thus, we hypothesize that instability of synapses from high expression of MARK4 makes the synapses vulnerable to tau and A? aggregates, which contributes to their eventual loss in AD. Thus, NDAN subjects would have a resistance toward the toxic protein aggregates owing to the resilience of their synapses due to low MARK4 levels. The purpose of this project is to better determine the role of MARK4 in AD to evaluate its importance at early stages of AD. This project will test the hypothesis that increased levels of MARK in AD makes their synapses susceptible to toxic protein aggregates leading to synaptic demise and ultimately the loss of neurons. However, several important questions remain. We will use complementary Drosophila and mouse models, as well as complementary molecular, electrophysiological, and behavioral techniques to answer key questions. Specific Aim 1 will determine whether synapse instability induced by overexpression of Par-1 leads to synapse loss. Specific Aim 2 will determine the mechanism of synapse instability induced by elevated levels of Par-1. Specific Aim 3 will test whether MARK4 overexpression exacerbates cognitive deficits and synapse dysfunction in current AD mouse models. Successful completion of this proposal will provide critical insights into early stages of AD like neurodegenerative diseases.